Phthalein and fluorescein derivatives



, 2,980,696 PHTHALEIN AND FLUQRESCEIN DERIVATIVES Jii'i Kiirbl, 1327 Zdenka Nejedleho, Lysa nad Labem,

Czechoslovakia No Drawing. Filed on. 10,1957, Ser. No. 689,254 Claims priority, application Czechoslovakia Oct. 16, 1956 7 Claims. (Cl. 260-427) The present invention relates to a new method of producing phthalein and fluorescein derivatives and more particularly to a method which can be utilized for the production of derivatives which could not be produced by any known method.

It is a primary object of the present invention to provide a simple method of producing phthalein and 11000320 omcoo'n canbe produced as well as fiuorescein derivatives having the following general formula:

(II) R R O 0 HOOCH C CHzCOOH NHzC O CH2N HOOCHzC 'l I CHzCOOH R O\R 'In'these formulas'the substituent-R may. be hydrogen,

ttes PatentC an alkyl radical such as methyl, ethyl, isopropyl-orthe like, or a halogen atom such as chlorine or bromine. The substituent X is CO or S0 The above formulas represent the probable structure of the compounds in solid 'or non-ionized state. It is to be understood that wherever Formulas I and II areset forth herein they are also meant to include the structures 1 and II, re-

,spectively, as'set forth below which are the probable 1 structures in aqueous solution orionized state, and vice on Hooomo I omcoon NHzC CHN .3 'ieroo'o'rnc omooon The class of compounds producedin accordance with the present invention'include -bis-N,N-dicarboxymethylarninomethyl derivatives of phenolphthalein-, oecre solphthalein, m-cr'esolphthalein, thymolphthaleiin;fluorescein, phenolsulfonphthalein, dichlorophenolphth'alein,1di-

bromophenolphthalein, Xyle'nolphthalein, dichlorophenoltions. The compounds of the present invention are suitable for this purpose both in alkaline and in acid solutions.

Attempts to produce bis-derivatives of the type produced herein by alkaline condensation of cresolphthalein, phenolphthalein and fiuor es'cein with imino diacetic acid and formaldehyde result in the production of compounds which are contaminated with undesired by-products which are injurious for analytical purposes. These by-products consist of: (1) unreactedphthalein dyestuff used as starting material;

(2) N,N-dicarboxymethyl-aminomethyl monode briefly mono-derivatives;

(3) ballast condensation products of the starting phthalein dyestuffwith formaldehyde alone, i.e. higher molecular compounds in which many molecules of the starting phthalein dyestutf are cross-linked by methylene bridges; and

(4) diiierent dicarboxymethyl aminomethyl derivatives of above. I

These by-products cannot be easily removed by known methods since their solubility closely approaches that of the desired final products. Some of them are even less soluble than the desired products so that they are concentrated therein by precipitation with acids during the-isolation-process.. r Theknown alkaline condensationlcannot"be used gem e'rally; if e.g. xylenolsulfonphthaleinor thy rnol'sulforl- "phthalein arerused 'as starting material; the reaction productsv consist almost entirely of the ballast by produ'ots. Moreover,.the sulfonphthalein derivatives cannot be purified .by known methods at all.

. -It is a further object of. the present invention to provide a method of condensing phthalcins and'. fluoresceins with imino diacetic acid andformaldehydewhile avoiding all of the above set'forth difliculties of carrying ont such 'condensations in alkaline medium. In accordance -with' the present invention the condensation isfcarried outin ac'id medium in the presence of gmonovalent cati'ohs "Sllchf as alkali metal :or ammonium cations in a -concentration which is sufiicient to maker, the .zp'htl'ialein "Kor ft and/ or the imino diacetic acidat least partially oluble 1 in the medium which remains strongly'acid. C

the condensation products mentioned in (3)v esbein' The method of the present invention can result in the production of new bis-derivatives which cannot be produced by alkaline condensation at all but which can be easily. prepared by the method of the present invention. Among the new compounds that may be prepared by the acid condensation method of the present invention are In accordance with the method of the present invention Lthc'phthalein derivative of the following general formula:

or the fluorescein derivative of the following general formula: I V V wherein R and X have the above set forthdefinitions, is heated with formaldehyde and imino diacetic acid in an acid medium, preferably a lower aliphatic carboxylic acid solution, such as acetic acid, in the presence of monovalent cations such as alkali metal'or ammonium cations, which are necessary to bring at least one or both of the acidic reaction components, i.e. the'imino diacetic acid or the phthal'ein or fluorescein derivative, at least partially into the solution; The resulting bis-derivative maythen be easilyisolated, for example by concentration ofthereaction mixture, e.g. byevaporation, and precipitation' of'the derivative by means of a polar organic solvent, particularly a lower-aliphatic alcohol such as ethanol. If necessary the recovery'proces's' maybe repefated by renewed dissolution of the precipitate in Water. and further precipitation by rneans of a polar organic solvent.-

The required cations may be added e.g. in the form of alkali metal or ammonium salts of lower aliphatic carboxylic acids, for instance of the ones used as solvents or reaction components, or alsov of any other appropriate acid. It is. thus possible to use corresponding salts of imino diacetic acid instead of the free acid itself; It has been tound, that it is possible to add such an. amount of said cations, that the. strongest, acid groups present are neutralized, e.g. the SO H groups or one of the carboxylic groups of'the imino diacetic acid component, the

strongly acid reaction of the medium being maintained.

end iri a short period of time, and the reaction products are practically free of the undesired higher molecular byproducts. The isolation is thus easy and the yields are unusually high.

The isolation method, mentioned above, consisting in precipitating the product with a low polar solvent such as with ethanol, is possible only in connection with the acid condensation according to the present invention. Salts of the desired bis-derivatives are thereby precipitated first of all, having 2-3 acid groups in their molecule neutralized with alkali metal or ammonium cations. Salts of mono-derivatives. however, formed but in a small amount, together with salts of the unreacted starting compounds, are substantially more soluble and remain in the mother liquor. The desired bis-derivative salts may be obtained in entirely pure condition and in very high yields by a further recrystallization of the precipitate from aqueous lower aliphatic alcohols with an appropriate pH-value, obtained for instance by addition of sodium acetate or of its mixture with free acetic acid; such a recrystallization causes almost no losses of the bis-derivatives.

The above described isolation method cannot be used in connection with the alkaline condensation, during which salts with all neutralized acid groups are formed. Such salts do not sufficiently differ in their solubility from the salts of the by-products and unreacted starting compounds. I

A very important advantage of the acid condensation of the present invention is the absence of higher molecular condensation products of the starting phthalein derivatives with formaldehyde, which, on the contrary, are formed in considerable amounts during alkaline condensation.

Further research work showed that the pure bis-derivatives. obtainable easily by the presentprocess, are most useful as indicators with distinct color change related to the metal ions concentration changes. 7 Only these bis-derivatives form symmetric resonance structures with high'color intensity and maximal shade depth. The presence of even small amounts of the unreacted starting phthalein, dvestufi or of its mono-substituted derivative causes troubles in that the expected hue appears prematurelv or. in the case of the fluorescein derivatives, a residual fluorescence is observed during the pH-changes of the solution. Similar troubles are caused by the higher molecular condensation products of the kind mentionedabove. The color [transitions are ,then unduly long and inexact. so that the reaction with metal ions cannot be exactlv established. Thus, for instance, in complexometric titration of alkaline earths with o-cresolphthalein' bis-derivative, obtained by alkaline condensation, a transition from deep violet into clear violet occurs at the point-of equivalence; with the corresponding pro duct of the acid condensation obtained according to the present invention a sharp transition from deep violet into colorless 7 is achieved. Similarlv, with sulfonphthalein bis-derivative'obtained bv alkaline condensation, the premature red coloration, appearing with decreasing pH-value, troubles exact color transition. This is en ages? hot so, however, with the same indicatorfprep ared acid condensation according to the invention.

7 Simultaneously all mentioned impurities unflavoi ably properties. Similar derivatives known hitherto contain different amounts of impurities and their properties thus vary from one batch to another. V

Among new substances, which could be obtained only the method. forming the object of the invention,

there are some possessing, new and useful, unexpected properties. Thus, for example, the thymolphthalein bisderivative, yields blue coloration with ions of Mn, Mg, Ca, Sr and Ba; in complexometric titration the solutions of said ionsrare decolored.,The indication extent is thereat shifted to higherpHvalues, in comparison with 0,-cresolphthalein and phen'olphthalein bis-derivatives, and this circumstance is ,particularlyimportant for complexometric evaluation of strontium and barium.v

Bis-derivatives of phenolsulfonphthalein, dichloroand dibromophenolsulfonphthalein, and m-cres'olsulfonphthalein display characteristic color reactions in acid medium with ions of Zr, B i Th, Sc, La, and other rare earth elements; Fe, AL'Zn, Pb, Cu, Ni, Co, Hg, Cd, Mn and others. Thymolsulfonphthalein xylenolsulfonphthalein show, in addition to said reactions in acid medium, also characteristic color reactions in alkaline medium, for instance, with ions of Zn, Pb, Vd, Cu, Ni, Co, Mn, Mg, Ca, Sr and Ba; this is made possible by unexpected, favorably changed course of acido-basic coloration properties of these bis-derivatives in comparison with the starting compounds, viz. thymolsulfonphthalein and xylenolsulfonphthalein. Both these new bis-derivatives may be used, if prepared. by the present method, as universal metallochrome indicators.

The following examples will more fully illustratethe method of the present invention. It is to be understood that the scope of the invention is not meant to be limited to the specific details of the examples.

Example 1 66 parts of finely'comminuted fluorescein, 53 parts of imino diacetic acid, 80 parts of sodium acetate (trihydrate) and 40 parts of 37% aqueous formaldehyde solution are mixed with 500 parts of glacial acetic acid. The mixture is heated in a close'dvessel, while shaking solved, which usually requires 2-8 hours. Thereafter about half of the volume is distilled-off and the residue is cooled down and precipitated by adding 1000-2000 ml, of ethanol. The precipitate is sucked off; washed with and I ethanol and ether and air-dried. The yield is at least 120 ,5.

parts, i.e. 81.5% of the theoretical amount, of the raw sodium salt ofbis-N,N-dicarboxymethyl-aminomethyl- I fluorescein. The raw sodium salt isdissolved in 36 0'parts of water, WhereafteriZO parts of saturatedsodium acetate solution and 4800 parts of ethanol'are added. After havk I ing been left standing for --two hours the clear liquidfis decantedand the residue is mixed with a surplus of;

ethanol.

; After-1-3 days standing the crystalline salt," is sucked-oil, washed'with ethanol and dried. Instead of sodium acetate and iminodiacetic acid it is possible to use the corresponding amount of sodium imino diacetate p O-Cresolphthale m i together with free imino diacetic acid. Th'e prdduct possesses the following structure:

0 HO OH solution the fluorescence appears again when traces of some metal salts; e'.g. those of calcium are added; and disappears again with addition of a suitable chelata'tion agentc'onverting free metal ions into complexes.

'Analogous bis-derivatives were prepared-when using phenolphthalein, o-crescilphthalein; xylenolphthalein or thymolphtlialeinas starting materials, in yields. between 70 and of the theoretical amount. I" 7 Using the following compounds (set forth in the lefthand column) as startingmaterials, the condensation productspossess the illustrated structures:

Phenolplith'alein on, on; on: on,

Their diluted aqueous solutions react at-suitable into yellow when strongly diluted.

It is a black, fine-crystalline substance, dissolving in 2-3 partsof water to an ink-blue solution changing its color Diluted, strongly acid solutions with pH less than zero are intensively red. Solutions with pH between zero and 6.5 have pure yellow color; at pH 6.5-8.5 they turn into clear blue, between pH.-l0.5-11.5'-into greyish yellowand above .12.7 into deep blue. The indicator forms with many cationsbetween pH 0-12.7 intensively blue colored chelates (complex compounds), 7 Analogous.bis-derivatives were prepared from pheno1- sulfonphthalein, 0- and.m-cresolsulfonphthalein, xylenol- .sulfonphthalein and the like, using the method described above. The obtained condensation products are dark red till black crystalline, easily water-soluble substances. Some of them, e.g. the. xylenolsulfonphthalein, are in their behaviour very similar to the thymolsulfonphthalein bis-derivative. Other derivatives, such as 0- or m-cresolsulfonphthalein or phenolsulfonphthalein derivatives react with cation's'also both in acid and alkaline mediurm characteristic color changes are produced, however, particularly in acid medium. 'Dichloroor dibromophenolsulfonphthalein may be also used as startthe indication pH extent rises in the series o'fphenol phthalein, xylenolphthalein and thymolphthalein bisderivatives. 7 r

Example 2 8 parts of sodium irnino diacetate are heated with 50 parts of glacial acetic acid until a clear or milk-like turbid solution is obtained, which is then cooled down to the room temperature. Thereafter 9.3 parts of thymolsulfonphthalein are dissolved therein and finally 4 parts of a 37% aqueous formaldehyde solution are added.- The closed vessel with the reaction mixture is left standing until the next day at room temperature and then the mixture is further heated for 8 hours at 50 C. The reaction is finished when the solution, prepared from one drop of the reaction mixture and 50-100 m1. of distilled water, does not change its yellow color into red after addition of 5 ml. of normal nitric acid, and when another solution, prepared from one drop of the reaction mixture and 50-l00 ml. of water, acidified with 1 ml. of normal nitric acid, changes it yellow color into blue after addition of a few drops of 0.05 normal solution of thorium tetranitrate. The isolation and purificacs3 CH3 or cHl on i tion'is carried out in the same way as in Example 1. The 1 ing compounds; in this case it is more advantageous to carry out the condensation'at higher temperatures, i.e. at about 70 C. The test reactions, indicating the accomplishment of the process, shouldbe fitted to known color changes of the starting sulfonphthaleins.

7 When theifollowing compounds are used as starting material, then the products, of the acid condensation have the structure illustrated below: o-Cresolsulfonphthalein CHa m-Cresolsulfonphthalein The dibromophenolsulfonphthalein bis-derivative possesses an analogous structure to the dichloro compound shown above the only difference being the substitution of Br in the formula for the Cl.

Among the new derivatives whichhave been prepared as set forth {above are the bis-derivatives of phenolsulfonphthalein, dichlorophenolsulfonphthalein, dibromophenolslllfonphthalein, o-cresolsnlfonphthalein, m-cresolsul- I'Onphthalein, xylenolsulfonphthalein and thymolsulfonphtha'lein.

Without further analysis, the foregoing will so fully reveal the gist of the present invention that otherscan vby applying current knowledge readily adapt it for various applications without omitting features that, from the standpoint vofnprior art, fairly constitute essential char; ,acteristics of the generic or specific aspects .of this invention and, therefore, such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claims.

What is claimed as new and .desired'to be secured by Letters Patent is:

1. A method of producing a compound selected from the group consisting .of I e neonate I cmooorr 7 C CH: 7

30001110 V cmcooH r HO ,OH

nooomo t j cmooorr sewees E on - K R 0 I and R R O v HO OH wherein R- and X have the same definitions as-above "as insoluble reactant with imino diacetic acid as insolu- 50-70 C. in a medium of a lower aliphatic monocarboxylic acid in the presence of a salt of one of said acids and a monovalent cation, said monovalent cationbeing selected fromthe group consisting of alkali metal and ammonium cations and being present in an amount sufficient to dissolve at least one of said insoluble reactants, thereby forming the corresponding compound; and' recovering the thus formed compound. I v

2. A method of producing a compound selected from the group consisting of:

on I

cmcoon omN omooon V o 7 V noocmc 'cniooon V RNHQC cm' 7 Hooomc 5 03200011 ble reactant and with formaldehyde at a temperature of i1 12 andSO comprising the steps of heating a substance and 80,, comprising the steps of heating azsubstance selected from the group consisting of:, selected from the group consisting of:

and g a and f n a i 0 H0 no on m wherein R and X have the same definitions asabove as insoluble reactant with imino diacetic acid as insoluble reactant and with formaldehyde in a medium of a lower aliphatic monocarboxylic acid at a temperature of wherein R and X have the same definitions as, above as insoluble reactant with imino diacetic acid as insoluble 'reactant'and with formaldehyde at a temperature of o 5040s C. in a medium of a lower aliphatic monocar 50-70 C. 1n the presence ofasalt of one of saidracids and boxylic acid in the presence of a salt of one of said acids g g g canon sald il 9 and an alkali metal cation,isaid alkali metal cation being ec e group E mg a a 1 me a ,an l pres ent in an amount suflicient to dissolve at least one monium canons and bemg F P m an amount Sufficient of Said insoluble reactants thereby forming the corre to dissolve at least one of said insoluble reactants, theresponding compound' and recovering the thus formed 40 by formmg the correpondlpg compound; fopce.ntratlng compound the thus formed reactlon mixture; and prectptta tlng said 3. A method of producing a compound selected from compound by means of a lower ahphatlc l h polar organic solvent. 7 1 g l t m of conslr'stmg 4. A method of producing a compound selected from R the groupconsisting of:

HO on nooomc omooon f p I 7 NHQC" o CHN 1 noocno Ho 0.1.: on I 110001110 H a. a a cnicoon 7 o (R a Nmo CHQN I M X e I ooomc i i omcoon f i t t j 7;

and

no OH HQOCHC /CH.COOB; i I HOOCHzC gmcoon noocmo cmooon V55 2299 1;:9 cntcqcn ,wbrein R is selected from theqgroup.consisting ofahydr oge'n methyl," ethylisopropyl, chlorine and bromine wherein R is selected from the group consisting offhpa ,sts z seea xtei aglesudt sqaljlth stauncw isfinsntfit? ftfi es ny l ethyl; 11mins and W r 13 i .t i4. atoms, and X is selected from the group consisting of'CO atoms, and 'Xis =s'elected'irom thejgroup consisting' of and S0,, comprising the steps of heating a substance seand 80;, comprising the steps of heating a substance lected from the groupconsisting-of: I, selected from the group consisting of:

R R .t .5

and

wherein R and X have the same definitions as above as wherein R and X have the same definitions as above as insoluble reactant WilZhJiIl'liIlO diacetic acid as insoluble insoluble reactant with imino diacetic acid as insolu- 'e c and With formaldehyde in a d m f a lo er 'i'i ble reactant and with formaldehyde at a temperature of aliphatic monocarboxylic acid at atemperature of 5O-70 50-70 C. in a medium of a lower aliphatic monocar- C. in the presence of' a salt of one of said acids and an boxylic acid in the presence of a sodium salt of one of alkali metal cation, said alkali metal cation being present saidaeids, said zsqdium; being presentin an amountsufin an amount sufficient to dissolve at least one of said ficie'nt to dissolve at least one of said insoluble reactants,

insoluble reactants, thereby forming the corresponding thereby forming the corresponding compound; concencompound; concentrating the thus formed reaction mix- 40 tratingthe thus formed reaction mixture; and precipit-atture; and precipitating said compound by means of a" ing said compound by means of ethyl alcohol. I 7 lower aliphatic alcohol. '6. A method, of producing a compound selected from 5. A method of producing a vcompound selected from the groupconsisting of': y I p I a the group consisting of: v

"on" x T nooomo omooon V V NHnC CHzN noocmc cmcoon and t 0H OH 110001110 cmcoon CHzfC OQH V p NHZCv v :CHEN H I a 1. 'nooemo cmooon I I CHQQO c;

i: "wherein is'selectedfromthe'group consisting of wherein R is selected from the'jigroup consistingicf hydro j "-.methyl, eth 1 isopropyl, eh-1or'ine 1;i and bromine geramethyl, ethyl, isopropy1, chlorine and fbromine atoms," andX is' selected from, the group consistinglof CO e and SO comprising the steps of heating a substance selccted from the group consisting of:

no on and wherein R and X have the same'definitions as above as insoluble reactant with imino diacetic acid as insoluble reactant and with formaldehyde at a temperature of 50-70 C. in a medium of acetic acid in the presence of sodium acetate in an amount sufiicicnt to dissolve at least one of said insoluble reactants, thereby forming the corresponding compound; and

recovering the thus formed compound.

7. A method of producing a compound selected f the group consisting of:

Hoocmo Nmc noocmc- (EH20 O OH CHtN CHaC O OH and r j.

' R I R a I I v V .f' g

HO OH HOOCH;;C\ /CH1CO0H NHzC CHIN a C HOOCIIzC CHCOOH R O\ R wherein R is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, chlorine and bromine atoms, and X is selected from the group consisting of CO and S0 comprising the steps of heating a substance selected from the group consisting of:

wherein R and X have the same definitions as above as insoluble reactant with imino diacetic acid as insoluble reactant and with formaldehyde at, a temperature of -70? C. in a'mediumof a lower aliphatic'monocarboxylic acid in the presence of an ammonium salt of one of said acids, said ammonium being present in an amount sufiicient to dissolve at least one of said insoluble rcactants, thereby forming the corresponding compound;

'and recovering the thus formed compound. 7

References Cited in the file of this patent UNITED STATES PATENTS Schwarzenbach May 15, FOREIGN PATENTS I I 298,194 Switzerland.. -.g m 1. 1954 

1. A METHOD OF PRODUCING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: 